Amino Acids Reference PDF

2 "The man who does not read good Structure & Function books has no advantage over the man who cannot read them."...

2 "The man who does not read good Structure & Function books has no advantage over the man who cannot read them." Mark Twain Introduction “It is structure that we look for, whenever we When we study life at the molecular level, it try to understand anything. All science is becomes apparent that the structures of bio- built upon this search. We like to logical molecules are inseparable from their understand, and to explain, observed facts in functions. The molecular interactions that terms of structure. un-derlie life are dependent on the structures - Linus Pauling of the molecules we are made of. 52 In this chapter, we will examine the nucleic acids, carbohydrates and lipids. structures of the major classes of The first three of these major groups are mac- biomolecules, with an eye to romolecules that are built as long polymers understanding how these structures re- made up of smaller subunits or monomers, late to function. like strings of beads. The lipids, while not chains of monomers, also have smaller subunits that are assem- bled in various ways to make the lipid components of cells, includ- ing membranes. The chemical properties and three dimen- sional conformations of these molecules determine all the mo- lecular interactions upon which life depends. Whether building structures within cells, transfer- ring information, or catalyzing reactions, the activities of biomo- lecules are governed by their Interactive 2.1 - The enzyme Hexokinase: as for all structures. The properties and enzymes, the activity of hexokinase depends on its shapes of macromolecules, in structure. Protein Database (PDB) turn, depend on the subunits of which they are built. Biological molecules As noted earlier, water is the most Building blocks abundant molecule in cells, and We will next examine the major groups of bio- provides the aqueous environment in logical macromolecules: proteins, polysac- which cellular chemistry hap-pens. charides, nucleic acids, and lipids. The Dissolved in this water are inorganic building blocks of the first three, respectively, ions like sodium, potassium and are amino acids, monosaccharides (sug- calcium. But the distinctiveness of ars), and nucleotides. Acetyl-CoA is the biochemistry derives from the vast most common building block of lipids. numbers of complex, large, car-bon compounds, that are made by living cells. You have probably learned that the major classes of biological molecules are proteins, 53 Structure & Function: Amino Acids "It is one of the more striking generalizations the vast assortment of proteins found in all liv- of biochemistry...that the twenty amino ac- ing cells. ids and the four bases, are, with minor reser- All amino acids have the same basic structure, vations, the same throughout Nature." which is shown in Figure 2.1. At the “center” - Francis Crick of each amino acid is a carbon called the α carbon and attached to it are four Building blocks of protein groups - a hydrogen, an α- YouTube Lectures All of the proteins on the face of by Kevin carboxyl group, an α-amine the earth are made up of the same HERE & HERE group, and an R-group, some- 20 amino acids. Linked to-gether times referred to as a side chain. in long chains called polypep- The α carbon, carboxyl, and amino tides, amino acids are the building blocks for groups are common to all amino acids, so the 54  lation. When this happens, these unusual amino acids can be incorporated into pro-teins. Enzymes containing selenocysteine, for example, include glutathione peroxi- dases, tetraiodothyronine 5' deiodinases, thioredoxin re- ductases, formate dehydroge- nases, glycine reductases, and selenophosphate synthetase. Pyrrolysine-containing pro- Figure 2.1 - General amino acid structure teins are much rarer and are mostly confined to archaea. R-group is the only unique feature in each amino acid. (A minor exception to this structure is that of proline, in which the end of the R-group is attached to the α- amine.) With the exception of glycine, which has an R-group consisting of a hy- drogen atom, all of the amino acids in pro- teins have four different groups attached to them and consequently can exist in two mirror image forms, L and D. With only very minor exceptions, every amino acid found in cells and in proteins is in the L configuration. There are 22 amino acids that are found in proteins and of these, only 20 are specified by the universal genetic code. The oth- ers, selenocysteine and pyrrolysine use tRNAs that are able to base pair with Table 2.1 - Essential and non- stop codons in the mRNA during trans- essential amino acids 55  Non-Polar Carboxyl Amine Aromatic Hydroxyl Other Alanine Aspartic Acid Arginine Phenylalanine Serine Asparagine Glycine Glutamic Acid Histidine Tryptophan Threonine Cysteine Isoleucine Lysine Tyrosine Tyrosine Glutamine Leucine Selenocysteine Methionine Pyrrolysine Proline Valine Table 2.2 - Amino acid categories (based on R-group properties) Essential and non-essential Non-protein amino acids Nutritionists divide amino acids into two There are also α-amino acids found in cells groups - essential amino acids (must be in that are not incorporated into proteins. Com- the diet because cells can’t synthesize them) mon ones include ornithine and citrulline. and non-essential amino acids (can be Both of these compounds are intermediates in made by cells). This classification of amino the urea cycle. Ornithine is a metabolic acids has little to do with the structure of precursor of arginine and citrulline can be amino acids. Essential amino acids vary con- produced by the breakdown of arginine. The siderable from one organism to another and latter reaction produces nitric oxide, an im- even differ in humans, depending on whether portant signaling molecule. Citrulline is the they are adults or children. Table 2.1 shows metabolic byproduct. It is sometimes used as essential and non-essential amino acids in a dietary supplement to reduce muscle fa- hu-mans. tigue. Some amino acids that are normally non- R-group chemistry essential, may need to be obtained from the We separate the amino acids into categories diet in certain cases. Individuals who do not based on the chemistry of their R-groups. If synthesize sufficient amounts of arginine, you compare groupings of amino acids in cysteine, glutamine, proline, selenocys- different textbooks, you will see different teine, serine, and tyrosine, due to illness, names for the categories and (sometimes) the for example, may need dietary supplements same amino acid being categorized differently containing these amino acids. by different authors. Indeed, we categorize ty- 56  Figure 2.2 - Amino acid side chain properties Wikipedia rosine both as an aromatic amino acid and ond only to leucine in occurrence. A D-form of as a hydroxyl amino acid. It is useful to clas- the amino acid is also found in bacterial cell sify amino acids based on their R-groups, be- walls. Alanine is non-essential, being read-ily cause it is these side chains that give each synthesized from pyruvate. It is coded amino acid its characteristic prop- for by GCU, GCC, GCA, and GCG. erties. Thus, amino acids with YouTube Lectures Wikipedia link HERE. by Kevin HERE & HERE Glycine (Gly/G) is the amino acid (chemically) similar side groups with the shortest side chain, hav- can be expected to func-tion in ing an R-group consistent only of a single similar ways, for example, during hydrogen. As a result, glycine is the only amino protein folding. acid that is not chiral. Its small side chain allows it to readily fit into both hydro-phobic Non-polar amino acids and hydrophilic environments. Alanine (Ala/A) is one of the most abundant amino acids found in proteins, ranking sec-  Leucine is encoded by six codons: Glycine is specified in the genetic code by UUA,UUG, CUU, CUC, CUA, CUG. Wikipedia GGU, GGC, GGA, and GGG. It is non- link HERE. essential to humans. Wikipedia link HERE. Methionine (Met/M) is an essential Isoleucine (Ile/I) is an essential amino amino acid that is one of two sulfur- acid encoded by AUU, AUC, and AUA. It has a containing amino acids - cysteine is the hydrophobic side chain and is also chiral in other. Methionine is non-polar and en- its side chain. Wikipedia link HERE. coded solely by the AUG codon. It is the “ini- tiator” amino acid in protein synthesis, be- Leucine (Leu/L) is a branched-chain amino ing the first one incorporated into protein acid that is hydrophobic and essential. chains. In prokary- otic cells, the first me- thionine in a protein is formy- lated. Wikipedia link HERE. Proline (Pro/P) is the only amino acid found in pro- teins with Figure 2.3 - Non-polar amino acids an R-group that joins with its own α-amino group, mak-ing Leucine is the only dietary amino acid re- a secondary amine and a ring. Proline is a ported to directly stimulate protein synthe- non-essential amino acid and is coded by sis in muscle, but caution is in order, as 1) CCU, CCC, CCA, and CCG. It is the least there are conflicting studies and 2) leucine tox- flexible of the protein amino acids and thus icity is dangerous, resulting in "the four D's": gives conformational rigidity when present in diarrhea, dermatitis, dementia and death. 58 a protein. Proline’s presence in a protein af- netic code by the codons GAU and GAC. fects its secondary structure. It is a dis- Wikipedia link HERE. rupter of α-helices and β-strands. Proline Glutamic acid (Glu/E), which is coded by is often hydroxylated in collagen (the reac- GAA and GAG, is a non-essential amino tion requires Vitamin C - ascorbate) and this has the effect of increasing the protein’s con- acid readily made by transamination of α- formational stability. Proline hydroxylation of ketoglutarate. It is a neurotransmitter hypoxia-inducible factor (HIF) serves as a and has an R-group with a carboxyl group sensor of oxygen levels and targets HIF for that readily ionizes (pKa = 4.1) at physiologi- destruction when oxygen is plentiful. cal pH. Wikipedia link HERE. Wikipedia link HERE. Amine amino acids Valine (Val/V) is an essential, non-polar Arginine (Arg/R) is an amino acid that is, in amino acid synthesized in plants. It is note- some cases, essential, but non-essential in oth- worthy in hemoglobin, for when it replaces ers. Premature infants cannot synthesize ar- glutamic acid at position number six, it ginine. In addition, surgical trauma, sepsis, causes hemoglobin to aggregate abnormally and burns increase demand for arginine. under low oxygen conditions, resulting in Most people, however, do not need arginine sickle cell disease. Valine is coded in the supplements. Arginine’s side chain contains a genetic code by GUU, GUC, GUA, and GUG. complex guanidinium group with a pKa of Wikipedia link HERE. over 12, making it positively charged at cellu- lar pH. It is coded for by six codons - CGU, Carboxyl amino acids CGC, CGA, CGG, AGA, and AGG. Wikipedia Aspartic acid (Asp/D) is a non-essential link HERE. amino acid with a carboxyl group in its R- group. It is readily produced by trans- amination of ox- aloacetate. With a pKa of 3.9, aspartic acid’s side chain is negatively charged at physiological pH. Aspartic acid is Figure 2.4 - Carboxyl amino acids specified in the ge- 59  Figure 2.5 - Amine amino acids Histidine (His/H) is the only one of the pro- and is necessary for optimizing growth of teinaceous amino acids to contain an pigs and chickens. Wikipedia link HERE. imida-zole functional group. It is an essential amino acid in humans and other Aromatic amino acids mammals. With a side chain pKa of 6, it can Phenylalanine (Phe/ F) is a non-polar, easily have its charge changed by a slight es-sential amino acid coded by UUU and change in pH. Protonation of the ring results UUC. It is a metabolic precursor of tyrosine. in two NH structures which can be drawn as Inability to metabolize phenylalanine arises two equally important resonant structures. from the genetic disorder known as phen- Wikipedia link HERE. ylketonuria. Phenylalanine is a component of the aspartame artificial sweetener. Lysine (Lys/K) is an essential amino acid Wikipedia link HERE. encoded by AAA and AAG. It has an R-group that can readily ionize with a charge of +1 at Tryptophan (Trp/W) is an essential physiological pH and can be post- amino acid containing an indole functional translationally modified to form acetyl- group. It is a metabolic precursor of sero- lysine, hydroxylysine, and methyllysine. tonin, niacin, and (in plants) the auxin It can also be ubiquitinated, sumoylated, phytohormone. Though reputed to serve as neddylated, biotinylated, carboxylated, a sleep aid, there are no clear research results and pupylated, and. O-Glycosylation of hy- indicating this. Wikipedia link HERE. droxylysine is used to flag proteins for ex- Tyrosine (Tyr/Y) is a non-essential port from the cell. Lysine is often added to amino acid coded by UAC and UAU. It is a animal feed because it is a limiting amino acid target for phosphorylation in proteins by tyrosine protein kinases and plays a role 60  three amino acids having an R-group with a hydroxyl in it (threonine and tyrosine are the others). It is coded by UCU, UCC, UCA, UGC, AGU, and AGC. Being able to hydrogen bond with wa- ter, it is classified as a polar amino acid. It is not essential for humans. Serine is precursor of many important cellular compounds, including purines, py- rimidines, sphingolipids, folate, and of the amino acids glycine, cysteine, and tryptophan. The hydroxyl group of serine in proteins is a target for phos-phorylation by certain protein ki-nases. Serine is also a part Figure 2.6 - Aromatic amino acids of the cata-lytic triad of serine proteases. Wikipedia link HERE. in signaling processes. In dopaminergic cells of the brain, tyrosine hy- droxylase converts tyro- sine to l-dopa, an immedi- ate precursor of dopa- mine. Dopamine, in turn, is a precursor of norepi- nephrine and epineph- rine. Tyrosine is also a pre- cursor of thyroid hor- mones and melanin. Wikipedia link HERE. Hydroxyl amino acids Serine (Ser/S) is one of Figure 2.7 - Hydroxyl amino acids 61  Figure 2.8 - Amino acid properties Wikipedia Threonine (Thr/T) is a polar amino acid ids bearing a hydroxyl group (serine and ty- that is essential. It is one of three amino ac- rosine are the others) and, as such, is a tar- 62 get for phos- phorylation in proteins. It is also a target for O- glycosylation of proteins. Threonine proteases use the hydroxyl group of the amino acid in their catalysis and it is a pre- cursor in one Figure 2.9 - Other amino acids biosynthetic pathway for with an amine from glutamine. Breakdown making glycine. In some applications, it is of asparagine produces malate, which can be used as a pro-drug to increase brain glycine oxidized in the citric acid cycle. Wikipedia levels. Threonine is encoded in the link HERE. genetic code by ACU, ACC, ACA, YouTube Lectures by Kevin Cysteine (Cys/C) is the only amino acid HERE & HERE with a sulfhydryl group in its side and ACG. Wikipedia link HERE. chain. It is non- essential for most humans, but may be Tyrosine - see HERE. essential in infants, the elderly and individu- als who suffer from certain metabolic dis- Other amino acids eases. Cysteine’s sulfhydryl group is readily Asparagine (Asn/N) is a non-essential oxidized to a disulfide when reacted with amino acid coded by AAU and AAC. Its car- another one. In addition to being found in boxyamide in the R-group gives it polarity. proteins, cysteine is also a component of the Asparagine is implicated in formation of ac- tripeptide, glutathione. Cysteine is specified rylamide in foods cooked at high tempera- by the codons UGU and UGC. Wikipedia link tures (deep frying) when it reacts with car- HERE. bonyl groups. Asparagine can be made in the body from aspartate by an amidation reaction 63 Glutamine (Gln/Q) is an amino acid that Like selenocysteine, it is not coded for in the is not normally essential in humans, but may genetic code and must be incorporated by be in individuals undergoing intensive athletic unusual means. This occurs at UAG stop co- training or with gastrointestinal disorders. It dons. Pyrrolysine is found in methano- has a carboxyamide side chain which does genic archaean organisms and at least one not normally ionize under physiological methane-producing bacterium. Pyrrolysine pHs, but which gives polarity to the side is a component of methane-producing en- chain. Glutamine is coded for by CAA and zymes. Wikipedia link HERE. CAG and is readily made by amidation of glu- tamate. Glutamine is the most abundant Ionizing groups amino acid in circulating blood and is one of pKa values for amino acid side chains are only a few amino acids that can cross the very dependent upon the chemical environ- blood-brain barrier. Wikipedia link ment in which they are present. For example, HERE. the R-group carboxyl found in aspartic acid has a pKa value of 3.9 when free in solu- Selenocysteine (Sec/U) is a component of tion, but can be as high as 14 when in certain selenoproteins found in all kingdoms of life. environments inside of proteins, though that It is a component in several enzymes, is unusual and extreme. Each amino acid has including glutathione peroxidases and thi- at least one ionizable amine group (α- oredoxin reductases. Selenocysteine is in- amine) and one ionizable carboxyl group (α- corporated into proteins in an unusual carboxyl). When these are bound in a pep- scheme involving the stop codon UGA. Cells tide bond, they no longer ionize. Some, but grown in the absence of selenium terminate not all amino acids have R-groups that can protein synthesis at UGAs. However, when ionize. The charge of a protein then arises selenium is present, certain mRNAs which from the charges of the α-amine group, the α- contain a selenocysteine insertion sequence carboxyl group. and the sum of the charges of (SECIS), insert selenocysteine when UGA is the ionized R-groups. Titration/ionization of encountered. The SECIS element has char- aspartic acid is depicted in Figure 2.10. Ioni- acteristic nucleotide sequences and secon- zation (or deionization) within a protein’s dary structure base-pairing patterns. Twenty structure can have significant effect on the five human proteins contain selenocysteine. overall conformation of the protein and, since Wikipedia link HERE. structure is related to function, a major im- pact on the activity of a protein. Most pro- Pyrrolysine (Pyl/O) is a twenty second teins have relatively narrow ranges of optimal amino acid, but is rarely found in proteins. 64  R-groups; or 4) other functional groups (such as sulfates or phos- phates) added to amino acids post- translationally - see below. Carnitine Not all amino acids in a cell are found in pro- teins. The most com- mon examples include ornithine (arginine me- tabolism), citrulline (urea cycle), and car- nitine (Figure 2.12). When fatty acids des- Figure 2.10 - Titration curve for aspartic acid Image by Penelope Irving tined for oxidation are moved into the mito- activity that typically correspond to the envi- chondrion for that purpose, they travel ronments in which they are found (Figure across the inner membrane attached to car- 2.11). It is worth noting that formation of pep- nitine. Of the two stereoisomeric forms, tide bonds between amino acids removes the L form is the active one. The molecule is ionizable hydrogens from both the α- amine and α- carboxyl groups of amino acids. Thus, ionization/ deionization in a protein arises only from 1) the amino terminus; 2) car- Figure 2.11 - Enzyme activity changes as pH changes Image by Aleia Kim boxyl terminus; 3) 65  Catabolism of amino acids We categorize amino acids as essential or non-essential based on whether or not an organism can synthesize them. All of the amino acids, however, can be bro- ken down by all organisms. They are, in fact, a source of energy for cells, particu- larly during times of starvation or for peo- Figure 2.12 - L-Carnitine ple on diets containing very low amounts of carbohydrate. From a perspective of synthesized in the liver from lysine and me- breakdown (catabolism), amino acids thionine. From exogenous sources, fatty ac- are categorized as glucogenic if they produce ids must be activated upon entry into the cyto- intermediates that can be made into glucose plasm by being joined to coenzyme A. The CoA portion of the molecule is replaced by carnitine in the intermembrane space of the mitochondrion in a reaction catalyzed by car- nitine acyltransferase I. The resulting acyl- carnitine molecule is trans- ferred across the inner mi- tochondrial membrane by the carnitine- acylcarnitine translo- case and then in the ma- trix of the mitochon- drion, carnitine acyl- transferase II replaces the carnitine with coen- Figure 2.13 - Catabolism of amino acids. Some have more Figure 6.88 zyme A ( ). than one path. Image by Pehr Jacobson 66 or ketogenic if their intermediates are made at all. In addition, N-linked- and O-linked- into acetyl-CoA. Figure 2.13 shows the glycoproteins have carbohydrates cova- metabolic fates of catabolism of each of the lently attached to side chains of asparagine amino acids. Note that some amino acids are and threonine or serine, respectively. both glucogenic and ke- togenic. Post-translational modifications After a protein is synthe- sized, amino acid side chains within it can be chemically modified, giv- ing rise to more diversity of structure and function (Figure 2.14). Common alterations include phos- phorylation of hy-droxyl groups of serine, threonine, or tyrosine. Lysine, proline, and his- tidine can have hydrox- yls added to amines in their R-groups. Other modifications to amino ac- Figure 2.14 - Post-translationally modified amino acids. Modifications shown in green. ids in proteins include ad- Image by Penelope Irving dition of fatty acids (myristic acid or palmitic acid), isopren- Some amino acids are precursors of important compounds in the body. Examples include oid groups, acetyl groups, methyl groups, epinephrine, thyroid hormones, L- iodine, carboxyl groups, or sulfates. dopa, and dopamine (all from tyrosine), These can have the effects of ionization (ad- serotonin (from tryptophan), and hista- dition of phosphates/sulfates), deionization mine (from histidine). (addition of acetyl group to the R-group amine of lysine), or have no effect on charge 67  Figure 2.15 - Phosphorylated amino acids Building polypeptides chain made up of just a few amino ac- YouTube Lectures Although amino acids serve ids linked together is called an oli- by Kevin other functions in cells, their HERE & HERE gopeptide (oligo=few) while a typi- most important role is as con-stituents of proteins. Pro-teins, as we noted earlier, are polymers of amino acids. Amino acids are linked to each other by peptide bonds, in which the carboxyl group of one amino acid is joined to the amino group of the next, with the loss of a molecule of water. Additional amino acids are added in the same way, by for- mation of peptide bonds be- tween the free carboxyl on the end of the growing chain and the amino group of the next Figure 2.16 Formation of a peptide bond amino acid in the sequence. A 68 cal protein, which is made up of many amino acids is called a polypeptide (poly=many). The end of the peptide that has a free amino group is called the N-terminus (for NH2), while the end with the free carboxyl is termed the C-terminus (for carboxyl). As we’ve noted before, function is dependent on structure, and the string of amino acids must fold into a specific 3-D shape, or confor- mation, in order to make a functional protein. The folding of polypeptides into their func- tional forms is the topic of the next sect